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Published on: October 27, 2009
Orbofiban: an orally active GPIIb/IIIa platelet receptor antagonist
N S Nicholson1, N A Abood, S G Panzer-Knodle
1Cardiovascular Discovery Research, Pharmacia Corp., 4901 Searle Parkway, Skokie, Illinois 60077, USA.
Abstract:
A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials.
Insights
Orbofiban, a GPIIb/IIIa antagonist, effectively inhibits platelet aggregation and thrombus formation in preclinical models. However, large clinical trials showed no significant clinical benefit despite potent platelet inhibition.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Thrombosis Research
Background:
- Platelet activation and thrombus formation are critical in acute coronary syndromes and restenosis.
- Aspirin and clopidogrel are standard antiplatelet agents, but broader spectrum agents are sought.
- First-generation oral GPIIb/IIIa antagonists showed promise but disappointing clinical trial outcomes.
Purpose of the Study:
- To evaluate the efficacy and safety of orbofiban, an oral GPIIb/IIIa antagonist, for antithrombotic protection.
- To assess orbofiban's potential for chronic oral administration in cardiovascular disease management.
Main Methods:
- Preclinical studies in canine models of thrombosis to assess antithrombotic effects.
- Pharmacokinetic evaluation of orbofiban's bioavailability and half-life.
- Clinical trials to assess platelet inhibition and clinical outcomes.
Main Results:
- Orbofiban demonstrated potent and specific inhibition of fibrinogen binding to GPIIb/IIIa, inhibiting platelet aggregation.
- Preclinical studies showed prevention of thrombus formation without major bleeding.
- Orbofiban exhibited favorable bioavailability (28%) and a long half-life (18 hr).
- Clinical trials confirmed orbofiban's pharmacodynamic effect of platelet inhibition but failed to show clinical benefit.
Conclusions:
- Orbofiban effectively inhibits platelet aggregation and thrombus formation in preclinical settings.
- Despite favorable pharmacokinetics and safety profile, orbofiban did not translate to clinical benefit in large-scale trials.
- Further research into GPIIb/IIIa antagonists requires careful consideration of clinical efficacy beyond platelet inhibition.
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